JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
R-B09

Signalment (JPC #1368171): Adult female New Zealand white rabbit

HISTORY: None

SLIDE A: HISTOPATHOLOGIC DESCRIPTION: Mucocutaneous junction, vulva (per contributor; 2 sections): Diffusely the epidermis is hyperplastic, thickened up to 3 times normal, characterized by acanthosis and anastomosing rete ridges, and there is increased intercellular edema with prominent intercellular bridging (spongiosis) and intracellular edema. There are multifocal erosions and ulcers with an overlying serocellular crust composed of necrotic debris admixed with serum, numerous degenerate heterophils, lymphocytes, and variably sized colonies of 2 x 4 µm bacilli and 2 µm cocci. Within the adjacent epithelium there is ortho- and rare parakeratotic hyperkeratosis. The superficial dermis is infiltrated by moderate numbers of macrophages, heterophils, and fewer lymphocytes and plasma cells that surround adnexa and blood vessels, transmigrate the epidermis and follicular epithelium, and infiltrate into and expand follicular lumina (mural and luminal folliculitis). Hair follicles are multifocally dilated and filled with lamellations of keratin. Multifocally in the superficial dermis, there is hemorrhage, fibrin, and edema, and lymphatics are ectatic.

SLIDE B: Warthin Starry 4.0: Multifocally the epidermis and inflammatory infiltrate contain low to moderate numbers of filamentous, argyrophilic, 0.2 µm wide by 15 µm long, spirochete bacteria.

MORPHOLOGIC DIAGNOSIS: Haired skin: Dermatitis and folliculitis, ulcerative, suppurative, and lymphohistiocytic, multifocal, moderate, with epidermal hyperplasia, orthokeratosis, and numerous argyrophilic spirochetes, New Zealand white rabbit (Oryctolagus cuniculus), lagomorph.

ETIOLOGIC DIAGNOSIS: Cutaneous treponemiasis

CAUSE: Treponema paraluis-cuniculi (formerly T. cuniculi)

CONDITION: Rabbit syphilis, vent disease, venereal spirochetosis

GENERAL DISCUSSION:

• Disease is rare, seropositivity is occasional in laboratory rabbits and has been reported in wild rabbits in Britain
• Contagious but not zoonotic
• Treponema are gram-negative, filamentous, microaerophilic, spirochetes

PATHOGENESIS:

• Transmission: Disease is transmitted via contact with infected skin; venereal spread is the most important route of transmission; also transmitted through extragenital direct contact, and from contact between young rabbits and infected dams
• There is no evidence of intrauterine transmission
• Bucks are often asymptomatic carriers and can spread disease to multiple does
• Asymptomatic carriers occur, with recrudescence when under stress

TYPICAL CLINICAL FINDINGS:

• Young rabbits are relatively resistant
• Susceptibility to disease appears to be strain-related
• Lesions can be painful, resulting in decreased breeding activity
• Colony epidemics can result in metritis, retained placentas, neonatal deaths, and decreased conception rates

TYPICAL GROSS FINDINGS:

• Initial lesions include edema, erythema, and papules at mucocutaneous junctions (vulva, prepuce, anal region, muzzle)
• Lesion progression to ulceration and crusting
• +/- Regional lymph node hyperplasia
• Bucks can have small star-shaped scars on their scrotum

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Lesions primarily confined to epithelium, including epidermal hyperplasia, necrosis, acanthosis, erosions, and ulcerations, with infiltration by plasma cells, macrophages, and heterophils
• Regional lymph node hyperplasia

ADDITIONAL DIAGNOSTIC TESTS:

• Definitive diagnosis requires demonstration of spirochetes in typical lesions:
  • Recommended test is wet mount preparation of lesion scrapings with dark field examination
• Silver stains of histologic section is used but has low sensitivity
• Serology is reliable but false negatives are possible; antigen and antibody tests are available
• The organism has yet to be successfully cultured

DIFFERENTIAL DIAGNOSIS:

• Moist dermatitis
• Pasteurella multocida: snuffles, conjunctivitis, and genital tract infections
• Traumatic lesions
• Dermatophytosis: Trichophyton mentagrophytes is most common; affects head and ears
• Acariasis: Psoroptes cuniculi (ear mites); Notoedres cati, and Sarcoptes scabiei (dermatitis of the face, nose, lips, and external genitalia)
• Myxomatosis: Leporipoxvirus; mucopurulent conjunctivitis

COMPARATIVE PATHOLOGY:

• NOT zoonotic, disease is restricted to rabbits
• Other diseases associated with other treponemes:
  • Horse: Although the cause of equine proliferative pododermatitis (“equine canker”) is unknown, Treponema have been associated with some cases
    • A recent study (Apprich, Vet Pathol. 2017) indicates that there is no immunohistochemical evidence of increased proliferative activity (i.e. Ki67 and PCNA labeling) of the dermal papillary body but that a key event in development is dysregulation of keratinocyte differentiation
  • Cattle: Treponema are reported amongst secondary invaders in bovine papillomatous digital dermatitis (PDD, AKA footwarts or hairy heel warts), with primary infection often by Dichelobacter nodosus; it is proposed that proliferation of treponemes (probably multiple species) causes the proliferative lesions
  • Cattle, and to a lesser extent sheep, goats, and wild elk: Bovine digital dermatitis (BDD) is a polymicrobial infection involving several Treponema (T. phagedenis, T. pedis, T. medium) and other anaerobic bacteria e.g. Fusobacterium necrophorum, Dichelobacter nodosus (D. nodosus not found in sheep BDD); these treponeme-associated hoof lesions have markedly different gross appearances between species despite isolation of the same treponemes
    • A recent study (Frossling, J Vet Diagn Invest. 2018) shows that ELISA analysis for phagedenis-like antibodies in serum or milk from dairy cows can identify animals with BDD
    • A recent study (Clegg, J Comp Pathol. 2016) identified digital dermatitis-associated treponemes from 100% of cattle limb pressure sores, especially deep within wounds and associated hair follicles, and not from normal skin microbiota
• Sheep: Treponema are implicated as playing a role in contagious ovine digital dermatitis (CODD), a severe syndrome recently reported in the UK; a recent study (Angell, J Comp Pathol. 2015) shows that etiopathogenesis is specifically associated with three phylogroups of Treponema: T. medium/T. vincentii-like, T. phagedenis-like, and T. pedis; CODD is differentiated from virulent footrot by its severity, lack of interdigital lesions, and poor response to conventional therapy and vaccination
• Free-ranging elk: Treponeme-associated hoof disease (TAHD) is a recently-recognized debilitating progressive condition with similarities to bovine digital dermatitis and contagious ovine digital dermatitis (Han, Vet Pathol. 2019)
• Pigs: Ear necrosis (“necrotic ear syndrome”, “ulcerative spirochetosis of the ear”), affecting the lower to entire ear margin of 6-9 week old piglets, is thought to be caused by a Treponema bacterium
• Human: Syphilis is caused by Treponema pallidum

REFERENCES:

1. Angell JW, Crosby-Durrani HE, Duncan JS, Carter SD, Blundell R. Histopathological characterization of the lesions of contagious ovine digital dermatitis and immunolabeling of Treponema-like organisms. J Comp Pathol. 2015;153:212-226.
2. Apprich V, Licka T, Zipfl N, Tichy A, Gabriel C. Equine hoof canker: cell proliferation and morphology. Vet Pathol. 2017;54(4):661-668.
3. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 287.
4. Clegg SR, Crosby-Durrani HE, Bell J, et. al. Detection and isolation of digital dermatitis treponemes from bovine pressure sores. J Comp Pathol. 2016;154:273-282.
5. Crosby-Durrani HE, Clegg SR, Singer E, et. al. Severe foot lesions in dairy goats associated with digital dermatitis treponemes. J Comp Pathol. 2016;154:283-296.
6. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier.2018:494.
7. Frossling J, Rosander A, Bjorkman C, Naslund K, Pringle M. Detection of Treponema phagedenis-like antibodies in serum and bulk milk from cows with and without digital dermatitis. J Vet Diagn Invest. 2018;30(1):86-92.
8. Graham JE. Lagomorpha (Pikas, rabbits, and hares). In: Miller RE, Fowler ME. Fowler’s Zoo and Wild Animal Medicine. Vol. 8. St. Louis, MO: Elsevier; 2015: 378.
9. Han S, Mansfield KG, Bradway DS, et. al. Treponeme-associated hoof disease of free-ranging elk (Cervus elaphus) in southwestern Washington State, USA. Vet Pathol. 2019;56(1):118-132.
10. Hargis AM, Myers S. Integumentary system. In: Zachary JF, Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1124.
11. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Mobsy Elsevier; 2016:642, 644.
12. Njaa BL. The ear. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. Louis, MO: Elsevier; 2017: 1259.
13. Watson-Welder JH, Nally JE, Alt DP, Palmer MV, Coatney J, Plummer P. Experimental transmission of bovine digital dermatitis to sheep: development of an infection model. Vet Pathol. 2018;55(2):245-257.

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